PROJECT SUMMARY/ABSTRACT The overall objective of this functional bladder mapping study is to identify the spinal cord epidural stimulation (scES) configurations (anode/cathode selection, amplitude, frequency and pulse width) at the lumbosacral level that can promote neural control of bladder storage (capacity) and voiding efficiency after spinal cord injury (SCI). This comprehensive functional mapping study in both humans and animals in parallel involves a novel clinical application of a marketed Medtronic device for bladder dysfunction after SCI. The mapping (human and animal) and training (human) experiments address several specific objectives of the SPARC Program initiative per RFA-RM-15-018 including neural circuit maps regarding functional connectivity (Aim 1), neural plasticity related to stimulation (bladder training experiments ? Aim 2), variability (animal-to- animal and patient-to-patient), and research on what organ functions results from different types of stimulation (storage vs voiding and identifying any additional effects on bowel and/or sexual function). The long-term reduction in the cost to the health care system, care givers and society would be dramatic. SCI results in impairments of locomotor, sensory and autonomic functions, severely affecting overall health and quality of life. Proper bladder management post-SCI is necessary to decrease the risk of upper urinary tract disease, a major source of morbidity. Life-long urologic care is required for SCI individuals, yet most efforts treat symptoms but do not improve intrinsic function. Current therapies for bladder management after SCI include catheterization, pharmacologic and surgical interventions, functional electrical stimulation (peripheral), and urethral stents, but all have deleterious effects. We have exciting data from multiple individuals with severe injuries (AIS A and B) indicating improved bladder function after undergoing a widely implemented activity-based rehabilitation, locomotor training (LT), which includes stepping using body weight support on a treadmill with manual facilitation. In addition, we have intriguing preliminary data from several completely paralyzed individuals receiving scES in combination with task specific training that recovered standing and voluntary movement and showed improvements in both bladder capacity and voiding efficiency. Our most recent pilot data also indicate an immediate benefit of scES alone on bladder function. Thus, we propose to determine the functional gains that can be achieved in the storage and voiding phases of lower urinary tract function as a result of activation of spinal circuits with scES in humans with SCI and in a clinically- relevant rodent SCI model. We will test the general hypothesis that bladder capacity and voiding efficiency increases with scES post-SCI and to an even greater extent with scES bladder training over time. This proposal involves the collaboration of clinicians and scientists with extensive experience in animal and human SCI models. Our unique approach will utilize the expertise of a multi-disciplinary team (expertise in bladder function, neuromodulation, rehabilitation, engineering, and statistics) to 1) determine the optimal stimulation parameters for storage and voiding in SCI research participants already implanted with the scES Medtronic device (16-electrode array from L1-S1); 2) quantify the long-term effects of daily bladder training using optimal stimulation parameters (all the same research participants); 3) measurement of secondary benefits (bladder medication usage, susceptibility to urinary tract infections, indirect cardiovascular, bowel and sexual function benefits) of long-term bladder training; and 4) address with a small animal model the impact of location, lesion severity, chronicity and gender. Our innovative approach and novel application of this Medtronic Specify 5-6-5 device will allow us to determine specific types of scES needed for bladder function which will lay the groundwork for expedient translation of this promising technique to larger numbers of individuals with SCI in the next phase of the SPARC initiative, with additional refinement in parallel using a large animal SCI model (pig) that is currently under development within the Kentucky Spinal Cord Research Center.